Recent progress in our understanding of the basic genetic and biochemical cause of Lesch-Nyhan disease now allows a preventive program for control of this severe X-linked form of cerebral palsy. The feasibility of prenatal diagnosis, using cultured amniotic cells and gestational management, has been demonstrated with identification of seven affected males in 22 pregnancies at risk for the disease monitored during the past 11 years. In each instance the diagnosis was made sufficiently early that the parents' desire to terminate the pregnancy could be met. This demonstration makes imperative the eventual identification of all affected patients in the various high-risk groups. In this way the female relatives at risk for carrying this X-linked gene can be identified and altered to the need for monitoring of their pregnancies if they are to avoid producing affected children. The initial screening is being accomplished with two simple automated chemical tests and is based on the high ratio, in urine, of uric acid to creatinine. Morning urine samples are blotted onto filter paper, dried and sent to our laboratory for analysis. Seven new patients, not previously identified, have been found; six of them is the screening program and one among relatives of a known patient. We expect to screen a total of 30,000 patients in cerebral palsy clinics, neurology clinics, genetics clinics, and schools for the handicapped and mental hospitals. The diagnosis will be confirmed in each case by an enzyme assay on erythrocytes, and collection where possible of a 24-hour urine. Pedigrees will be obtained and heterozygote females identified. Improvements in the heterozygote test will be evaluated. Our objective is thus to demonstrate, in a pilot program, the applicability of this approach to preventive control of this disease and to evaluate the relative effectiveness of screening various population groups in identifying new patients with this disease, and through them the female carriers of the gene. We anticipate that it will serve as a model for use by state health departments or federal programs, after we determine the frequency of new cases found in various high-risk groups tested.